Despite improved tuberculosis control measures in the United States, tuberculosis continues to be a disease of growing worldwide importance. The currently-available drugs and vaccine (BCG) are efficacious, but are insufficient to prevent tuberculosis from continuing to spread and cause morbidity and mortality. An improved vaccine, developed and evaluated with better understanding of the mechanisms of protective immunity required for control of tuberculosis, has the theoretical potential of markedly improving prevention of tuberculosis. While it is clearly established that the cytokine, interferon gamma, is essential for protective immunity to tuberculosis, the mechanisms of interferon gamma in protective immunity are incompletely understood. In particular, the host genes whose expression is regulated by interferon gamma and that mediate protection against tuberculosis remain to be identified. While nitric oxide synthetase is one of these genes, there is strong evidence that additional interferon gamma-regulated genes contribute to control of tuberculosis. In this project, we propose experiments whose long term goal is to identify interferon gamma-regulated genes that are essential for immune control of tuberculosis. We will first characterize the course of M. tuberculosis infection in mice lacking each of three transcription factors (STAT1, IRF1, and ICSBP) that mediate the effects of interferon gamma on gene expression, to determine whether the interferon gamma-regulated genes that control M. tuberculosis in the lung are downstream of one or more of these transcription factors. In addition, we will prepare bone marrow chimeric mice, to determine whether macrophages are the only cells whose response to interferon gamma contributes to control of M. tuberculosis in the lungs. Finally, we will use high-density DNA microarrays to analyze gene expression in the lungs of M. tuberculosis-infected mice lacking each of the interferon gamma-responsive transcription factors, to determine the feasibility of this approach in identifying the genes that mediate interferon gamma-dependent protective immunity to tuberculosis. The studies proposed in this application will contribute to the knowledge of the molecular and cellular mechanisms of immunity to tuberculosis. In addition, they will determine the feasibility of analysis of gene expression in the lungs of specific strains of mice to ultimately identify genes that confer protection against tuberculosis.